Cyclocarbamate and cyclic amide derivatives

ABSTRACT

This invention provides compounds of the formula:  
                 
 
     wherein A and B are independent substituents selected from S, CH or N; provided that when A is S, B is CH or N; and when B is S, A is CH or N; and A and B cannot both be CH; and when A and B both equal N, one N may be optionally substituted with an C 1  to C 6  alkyl group; R 1  and R 2  are independent substituents selected from the group of H, C 1  to C 6  alkyl, substituted C 1  to C 6  alkyl, C 2  to C 6  alkenyl, substituted C 2  to C 6  alkenyl, C 2  to C 6  alkynyl, substituted C 2  to C 6  alkynyl, C 3  to C 8  cycloalkyl, substituted C 3  to C 8  cycloalkyl, aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR A , or NR B COR A ; or R 1  and R 2  are fused to form optionally substituted 3 to 8 membered spirocyclic alkyl, alkenyl or heterocyclic ring, the heterocyclic ring containing one to three heteroatoms selected from the group of O, S and N; or pharmaceutically useful salts thereof. The compounds of this invention are useful as agonists and antagonists of the progesterone receptor and in methods of inducing contraception and in the treatment or prevention of benign or malignant neoplastic diseases.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. patent applicationSer. No. 09/304,555, filed May 4, 1999.

FIELD OF THE INVENTION

[0002] This invention relates to compounds that act as agonists andantagonists of the progesterone receptor, their preparation, andutility.

BACKGROUND OF THE INVENTION

[0003] Intracellular receptors (IR) form a class of structurally relatedgenetic regulators known as “ligand dependent transcription factors” (R.M. Evans, Science, 240, 889, 1988). The steroid receptor family is asubset of the IR family, including progesterone receptor (PR), estrogenreceptor (ER), androgen receptor (AR), glucocorticoid receptor (GR), andmineralocorticoid receptor (MR).

[0004] The natural hormone, or ligand, for the PR is the steroidprogesterone, but synthetic compounds, such as medroxyprogesteroneacetate or levonorgestrel, have been made which also serve as ligands.Once a ligand is present in the fluid surrounding a cell, it passesthrough the membrane via passive diffusion, and binds to the IR tocreate a receptor/ligand complex. This complex then translocates to thenucleus of the cell where it binds to a specific gene or genes presentin the cell's DNA. Once bound to a specific DNA sequence the complexmodulates the production of the mRNA and protein encoded by that gene.

[0005] A compound that binds to an IR and mimics the action of thenatural hormone is termed an agonist, whilst a compound which inhibitsthe effect of the hormone is an antagonist.

[0006] PR agonists (natural and synthetic) are known to play animportant role in the health of women. PR agonists are used in birthcontrol formulations, typically in the presence of an ER agonist. ERagonists are used to treat the symptoms of menopause, but have beenassociated with a proliferative effect on the uterus (innon-hysterectomized women) which can lead to an increased risk ofuterine cancers. Co-administration of a PR agonist reduces or ablatesthat risk.

[0007] PR antagonists may also be used in contraception. In this contextthey may be administered alone (Ulmann, et al, Ann. N. Y. Acad. Sci.,261, 248, 1995), in combination with a PR agonist (Kekkonen, et al,Fertility and Sterility, 60, 610, 1993) or in combination with a partialER antagonist such as tamoxifen (WO 96/19997 A1 Jul. 4, 1996).

[0008] PR antagonists may also be useful for the treatment of hormonedependent breast cancers (Horwitz, et al, Horm. Cancer, 283, pub:Birkhaeuser, Boston, Mass., ed. Vedeckis) as well as uterine and ovariancancers. PR antagonists may also be useful for the treatment ofnon-malignant chronic conditions such as fibroids (Murphy, et al, J.Clin. Endo. Metab., 76, 513, 1993) and endometriosis (Kettel, et al,Fertility and Sterility, 56, 402, 1991).

[0009] PR antagonists may also be useful in hormone replacement therapyfor post-menopausal patients in combination with a partial ER antagonistsuch as tamoxifen (U.S. Pat. No. 5,719,136). PR antagonists such asMifepristone have also been shown to have bone sparing effects inrodents, and as such may be useful in the treatment of osteoporosisassociated with the menopause (Barengolts, et al, Bone, 17, 21, 1995).

[0010] PR antagonists, such as mifepristone and onapristone, have beenshown to be effective in a model of hormone dependent prostate cancer,which may indicate their utility in the treatment of this condition inmen (Michna, et al, Ann. N. Y. Acad. Sci., 761, 224, 1995).

[0011] Jones, et al, (U.S. Pat. No. 5,688,810) described the PRantagonist dihydroquinoline 1.

[0012] Jones, et al, described the enol ether 2 (U.S. Pat. No.5,693,646) as a PR ligand.

[0013] Jones, et al, described compound 3 (U.S. Pat. No. 5,696,127) as aPR ligand.

[0014] Zhi, et al, described lactones 4, 5 and 6 as PR antagonists (J.Med. Chem., 41, 291, 1998).

[0015] Zhi, et al, described the ether 7 as a PR antagonist (J. Med.Chem., 41, 291, 1998).

[0016] Combs, et al., disclosed the amide 8 as a ligand for the PR (J.Med. Chem., 38, 4880, 1995).

[0017] Perlman, et. al., described the vitamin D analog 9 as a PR ligand(Tet. Letters, 35, 2295, 1994).

[0018] Hamann, et al, described the PR antagonist 10 (Ann. N.Y. Acad.Sci., 761, 383, 1995).

[0019] Chen, et al, described the PR antagonist 11 (Chen, et al, POI-37,16^(th) Int. Cong. Het. Chem., Montana, 1997).

[0020] Kurihari, et. al., described the PR ligand 12 (J. Antibiotics,50, 360, 1997).

DESCRIPTION OF THE INVENTION

[0021] This invention provides compounds of Formula I:

[0022] wherein:

[0023] A and B are independent substituents selected from S, CH or N;

[0024] Provided that when A is S, B is CH or N; provided that when B isS, A is CH or N;

[0025] and A and B cannot both be CH;

[0026] and when A and B both equal N, one N may be optionallysubstituted with an C₁ to C₆ alkyl group;

[0027] R₁ and R₂ are independent substituents selected from the group ofH, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₂ to C₆ alkenyl,substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, substituted C₂ to C₆alkynyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl,substituted aryl, heterocyclic, substituted heterocyclic, COR^(A), orNR^(B)COR^(A);

[0028] or R₁ and R² are fused to form:

[0029] a) an optionally substituted 3 to 8 membered spirocyclic alkylring, preferably a 3 to 6 membered spirocyclic alkyl ring; or

[0030] b) an optionally substituted 3 to 8 membered spirocyclic alkenylring, preferably a 3 to 6 membered spirocyclic alkenyl ring; or

[0031] c) an optionally substituted 3 to 8 membered spirocyclic ringcontaining one to three heteroatoms selected from O, S and N, preferablya 3 to 6 membered spirocyclic ring containing one to three heteroatoms;

[0032] R^(A) is H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl,substituted aryl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, or substituted C₁ to C₃ aminoalkyl;

[0033] R^(B) is H, C₁ to C₃ alkyl, or substituted C₁ to C₃ alkyl;

[0034] R³ is H, OH, NH₂, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₃to C₆ alkenyl, substituted C₁ to C₆ alkenyl, alkynyl, or substitutedalkynyl, or COR^(C);

[0035] R^(C) is H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl,substituted aryl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, or substituted C₁ to C₃ aminoalkyl;

[0036] R⁴ is a trisubstituted benzene ring containing the substituentsX, Y and Z as shown below,

[0037] X is selected from halogen, CN, C₁ to C₃ alkyl, substituted C₁ toC₃ alkyl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃thioalkyl, substituted C₁ to C₃ thioalkyl, C₁ to C₃ aminoalkyl,substituted C₁ to C₃ aminoalkyl, NO₂, C₁ to C₃ perfluoroalkyl, 5 or 6membered heterocyclic ring containing 1 to 3 heteroatoms, COR^(D),OCOR^(D), or NR^(E)COR^(D);

[0038] R^(D) is H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl,substituted aryl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, or substituted C₁ to C₃ aminoalkyl;

[0039] R^(E) is H, C₁ to C₃ alkyl, or substituted C₁ to C₃ alkyl;

[0040] Y and Z are independent independently selected from H, halogen,CN, NO₂, C₁ to C₃ alkoxy, C₁ to C₃ alkyl, or C₁ to C₃ thioalkyl; or

[0041] R⁴ is a five or six membered ring with 1, 2, or 3 heteroatomsfrom the group including OS, SO, SO₂ or NR⁵ and containing one or twoindependent substituents from the group including H, halogen, CN, NO₂and C₁ to C₃ alkyl, C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, COR^(F), orNR^(G)COR^(F);

[0042] R^(F) is H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl,substituted aryl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, or substituted C₁ to C₃ aminoalkyl;

[0043] R^(G) is H, C₁ to C₃ alkyl, or substituted C₁ to C₃ alkyl;

[0044] R⁵ is H, or C₁ to C₃ alkyl;

[0045] Q is O, S, NR⁶, or CR⁷R⁸;

[0046] R⁶ is from the group including CN, C₁ to C₆ alkyl, substituted C₁to C₆ alkyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl,substituted aryl, heterocyclic, substituted heterocyclic, or SO₂CF₃;

[0047] R⁷ and R⁸ are independent substituents from the group includingH, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₈ cycloalkyl,substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocyclic,substituted heterocyclic, NO₂, or CN CO₂R⁹;

[0048] R⁹ is C₁ to C₃ alkyl;

[0049] or CR⁷R⁸ may comprise a six membered ring of the structure below:

[0050] W is O or a chemical bond or a pharmaceutically acceptable saltthereof.

[0051] Among the preferred compounds of this invention are those ofFormula I wherein:

[0052] A and B are independent substituents S, CH or N,

[0053] provided that when A is S, B is CH or N; and

[0054] when B is S, A is CH or N; and

[0055] A and B cannot both be CH; and

[0056] when A and B both equal N, one N may be optionally substitutedwith an C₁ to C₆ alkyl group;

[0057] R¹ is H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₈cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl,heterocyclic, substituted heterocyclic, COR^(A), or NR^(B)COR^(A);

[0058] R² is H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₂ to C₆alkenyl, substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, substituted C₂to C₆ alkynyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl,aryl, substituted aryl, heterocyclic, substituted heterocyclic, COR^(A),or NR^(B)COR^(A);

[0059] or R¹ and R² are fused to form:

[0060] a) an optionally substituted 3 to 8 membered spirocyclic alkylring; or

[0061] b) an optionally substituted 3 to 8 membered spirocyclic alkenylring; or

[0062] c) an optionally substituted 3 to 8 membered spirocyclic ringcontaining one to three heteroatoms selected from the group of O, S andN;

[0063] R^(A) is H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl,substituted aryl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, or substituted C₁ to C₃ aminoalkyl;

[0064] R^(B) is H, C₁ to C₃ alkyl, or substituted C₁ to C₃ alkyl;

[0065] R³ is H, OH, NH₂, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₃to C₆ alkenyl, substituted C₁ to C₆ alkenyl, alkynyl, or substitutedalkynyl, or COR^(C);

[0066] R^(C) is H, C₁ to C₄ alkyl, substituted C₁ to C₄ alkyl, aryl,substituted aryl, C₁ to C₄ alkoxy, substituted C₁ to C₄ alkoxy, C₁ to C₄aminoalkyl, or substituted C₁ to C₄ aminoalkyl;

[0067] R⁴ is a trisubstituted benzene ring containing the substituentsX, Y and Z as shown below:

[0068] X is taken from the group including halogen, CN, C₁ to C₃ alkyl,substituted C₁ to C₃ alkyl, C₁ to C₃ alkoxy, substituted C₁ to C₃alkoxy, C₁ to C₃ thioalkyl, substituted C₁ to C₃ thioalkyl, C₁ to C₃aminoalkyl, substituted C₁ to C₃ aminoalkyl, NO₂, C₁ to C₃perfluoroalkyl, 5-membered heterocyclic ring containing 1 to 3heteroatoms, COR^(D), OCOR^(D), or NR^(E)COR^(D);

[0069] R^(D) is H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl,substituted aryl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, or substituted C₁ to C₃ aminoalkyl;

[0070] R^(E) is H, C₁ to C₃ alkyl, or substituted C₁ to C₃ alkyl;

[0071] Y and Z are independent substituents taken from the groupincluding H, halogen, CN, NO₂, C₁ to C₃ alkoxy, C₁ to C₃ alkyl, or C₁ toC₃ thioalkyl; or

[0072] R⁴ is a five or six membered ring with 1, 2, or 3 heteroatomsfrom the group including O, S, SO, SO₂ or NR⁵ and containing one or twoindependent substituents from the group including H, halogen, CN, NO₂and C₁ to C₃ alkyl, or C₁ to C₃ alkoxy;

[0073] R⁵ is H or C₁ to C₃ alkyl;

[0074] Q is O, S, NR⁶, or CR⁷R⁸;

[0075] R⁶ is from the group including CN, C₁ to C₆ alkyl, substituted C₁to C₆ alkyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl,substituted aryl, heterocyclic, substituted heterocyclic, or SO₂CF₃;

[0076] R⁷ and R⁸ are independent substituents from the group includingH, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₈ cycloalkyl,substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocyclic,substituted heterocyclic, NO₂, or CN CO₂R⁹;

[0077] R⁹ is C₁ to C₃ alkyl, or CR⁸R⁹ comprise a six membered ring asshown by the structure below

[0078] W is O or a chemical bond or a pharmaceutically acceptable saltthereof.

[0079] Further preferred compounds are those of Formula I wherein:

[0080] A and B are independent substituents from the group including S,CH or N;

[0081] provided that when A is S, B is CH or N; and

[0082] when B is S, A is CH or N; and

[0083] A and B cannot both be CH;

[0084] R¹=R² and are selected from the group which includes C₁ to C₃alkyl, substituted C₁ to C₃ alkyl, or spirocyclic alkyl constructed byfusing R¹ and R² to form a 3 to 6 membered spirocyclic ring;

[0085] R³ is H, OH, NH₂, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, orCOR^(C);

[0086] R^(C) is H, C₁ to C₄ alkyl, or C₁ to C₄ alkoxy;

[0087] R⁴ is a disubstituted benzene ring containing the substituents Xand Y as shown below:

[0088] X is selected from the group including halogen, CN, C₁ to C₃alkoxy, C₁ to C₃ alkyl, NO₂, C₁ to C₃ perfluoroalkyl, 5 memberedheterocyclic ring containing 1 to 3 heteroatoms, or C₁ to C₃ thioalkyl;

[0089] Y is a substituent on the 4′ or 5′ position selected from thegroup of H, halogen, CN, NO₂, C₁ to C₃ alkoxy, C₁ to C₄ alkyl, or C₁ toC₃ thioalkyl; or

[0090] R⁴ is a five membered ring with the structure shown below:

[0091] U is O, S, or NR⁵;

[0092] R⁵ is H, or C₁ to C₃ alkyl, or C₁ to C₄ CO₂alkyl;

[0093] X′ is selected from halogen, CN, NO₂, C₁ to C₃ alkyl or C₁ to C₃alkoxy;

[0094] Y′ is H or C₁ to C₄ alkyl; or

[0095] R⁴ is a six membered ring with the structure:

[0096] X¹ is N or CX²,

[0097] X² is halogen, CN or NO₂;

[0098] Q is O, S, NR⁶, or CR⁷R⁸;

[0099] R⁶ is selected from the group including CN, C₁ to C₆ alkyl,substituted C₁ to C₆ alkyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈cycloalkyl, aryl, substituted aryl, heterocyclic, substitutedheterocyclic, or SO₂CF₃;

[0100] R⁷ and R⁸ are independent substituents selected from the group ofH, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₈ cycloalkyl,substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocyclic,substituted heterocyclic, NO₂, or CN CO₂R⁹;

[0101] R⁹ is C₁ to C₃ alkyl; or CR⁷R⁸ comprise a six membered ring ofthe structure:

[0102] W is O or a chemical bond; or a pharmaceutically acceptable saltthereof

[0103] Each of the generic and subgeneric groups of compounds herein mayfurther be divided into two further subgroups, one in which Q is oxygenand another wherein Q is selected from S, NR⁶, or CR⁷R⁸.

[0104] The compounds of this invention have been shown to bind to the PRand act as agonists and/or antagonists in functional models, eitherin-vitro and/or in-vivo. These compounds may be used for contraception,in the treatment of fibroids, endometriosis, breast, uterine, ovarianand prostate cancer, osteoporosis and post menopausal hormonereplacement therapy.

[0105] The compounds in the present invention contain a pendent aromaticsubstituent which may consist of aryl, substituted aryl, heteroaryl orsubstituted heteroaryl groups.

[0106] The compounds of this invention may contain an asymmetric carbonatom and some of the compounds of this invention may contain one or moreasymmetric centers and may thus give rise to optical isomers anddiastereomers. While shown without respect to stereochemistry in FormulaI, II, and III, the present invention includes such optical isomers anddiastereomers; as well as the racemic and resolved, enantiomericallypure R and S stereoisomers; as well as other mixtures of the R and Sstereoisomers and pharmaceutically acceptable salts thereof

[0107] The term “alkyl” is used herein to refer to both straight- andbranched-chain saturated aliphatic hydrocarbon groups having from one to8 carbon atoms, preferably from 1 to 6 carbon atoms; “alkenyl” isintended to include both straight- and branched-chain alkyl group havingfrom 2 to 8 carbon atoms, preferably 2 to 6 carbon atoms, with at leastone carbon-carbon double bond; “alkynyl” group is intended to cover bothstraight- and branched-chain alkyl group having from 2 to 8 carbonatoms, preferably 2 to 6 carbon atoms, with at least one carbon-carbontriple bond.

[0108] The terms “substituted alkyl”, “substituted alkenyl”, and“substituted alkynyl” refer to alkyl, alkenyl, and alkynyl as justdescribed having one or more substituents from the group includinghalogen, CN, OH, NO₂, amino, aryl, heterocyclic, substituted aryl,substituted heterocyclic, alkoxy, aryloxy, substituted alkyloxy,alkylcarbonyl, alkylcarboxy, alkylamino, arylthio. These substituentsmay be attached to any carbon of alkyl, alkenyl, or alkynyl groupprovided that the attachment constitutes a stable chemical moiety.

[0109] The term “aryl” is used herein to refer to an aromatic systemwhich may be a single ring or multiple aromatic rings fused or linkedtogether as such that at least one part of the fused or linked ringsforms the conjugated aromatic system. The aryl groups include but notlimited to phenyl, naphthyl, biphenyl, anthryl, tetrohydronaphthyl,phenanthryl.

[0110] The term “substituted aryl” refers to aryl as just defined havingone or more substituents from the group including halogen, CN, OH, NO₂,amino, alkyl, cycloalkyl, alkenyl, alkynyl, alkoxy, aryloxy, substitutedalkyloxy, alkylcarbonyl, alkylcarboxy, alkylamino, or arylthio.

[0111] The term “heterocyclic” is used herein to describe a stable 4- to7-membered monocyclic or a stable multicyclic heterocyclic ring which issaturated, partially unsaturated, or unsaturated, and which consists ofcarbon atoms and from one to four heteroatoms selected from the groupincluding N, O, and S atoms. The N and S atoms may be oxidized. Theheterocyclic ring also includes any multicyclic ring in which any ofabove defined heterocyclic rings is fused to an aryl ring. Theheterocyclic ring may be attached at any heteroatom or carbon atomprovided the resultant structure is chemically stable. Such heterocyclicgroups include, for example, tetrahydrofuran, piperidinyl, piperazinyl,2-oxopiperidinyl, azepinyl, pyrrolidinyl, imidazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, morpholinyl,indolyl, quinolinyl, thienyl, furyl, benzofuranyl, benzothienyl,thiamorpholinyl, thiamorpholinyl sulfoxide, and isoquinolinyl.

[0112] The term “substituted heterocyclic” is used herein to describethe heterocyclic just defined having one or more substituents selectedfrom the group which includes halogen, CN, OH, NO₂, amino, alkyl,substituted alkyl, cycloalkyl, alkenyl, substituted alkenyl, alkynyl,alkoxy, aryloxy, substituted alkyloxy, alkylcarbonyl, alkylcarboxy,alkylamino, or arylthio. The term “alkoxy” is used herein to refer tothe OR group, where R is alkyl or substituted alkyl. The term “aryloxy”is used herein to refer to the OR group, where R is aryl or substitutedaryl. The term “alkylcarbonyl” is used herein to refer to the RCO group,where R is alkyl or substituted alkyl. The term “alkylcarboxy” is usedherein to refer to the COOR group, where R is alkyl or substitutedalkyl. The term “aminoalkyl” refers to both secondary and tertiaryamines wherein the alkyl or substituted alkyl groups may be either sameor different and the point of attachment is on the nitrogen atom. Theterm “thioalkyl” is used herein to refer to the SR group, where R isalkyl or substituted alkyl. The term “halogen” refers to Cl, Br, F, andI element.

[0113] The compounds of this invention can be prepared following theSchemes illustrated below:

Cyclocarbamate Derivatives

[0114] Processes for Preparing Thiophene Cyclocarbamate Derivatives

[0115] A. Methods for synthesizing the thiophene cyclocarbamatecompounds depicted in Scheme 1 are described below:

[0116] Thus the amino thiophene ester 2 was prepared according to aliterature procedure involving the Gewald reaction (see ComprehensiveHeterocyclic Chemistry II. A Review of the Literature 1982-1995. A. R.Katritsky et al. Vol. 2 page 639), i.e. the reaction of a suitablysubstituted aromatic acetaldehyde with sulfur and methyl cyanoacetate inrefluxing methanol (Scheme 1). Reaction of the 2-amino group with asuitable chloroformate or carbonate affords the protected amine 3. Thiscan be accomplished by allowing 2 to react with a chloroformate orcarbonate derivative such as methyl chloroformate, ethyl chloroformate,allyl chloroformate, 2-(trimethylsilyl)ethyl chloroformate ordi-tert-butyldicarbonate in a solvent such as benzene, toluene, xylene,dichloromethane, tetrahydrofuran or pyridine. The reaction can becarried out under an inert atmosphere (nitrogen or argon) from 0° C. upto the reflux temperature of the solvent and may require the presence ofa base such as 4-dimethylaminopyridine, triethylamine, pyridine ordi-isopropyl ethylamine. Treatment of the protected amino compound 3with an organo-metallic reagent such as a Grignard reagent, an alkyl oraryl-zinc reagent, an alkyl or aryl lithium reagent in an inert solvent(tetrahydrofuran, diethylether) under an inert atmosphere (nitrogen orargon) at a suitable temperature from 0° C. up to reflux temperature ofthe solvent will then provide the tertiary alcohol 4. Compound 4 maythen be subjected to basic conditions to effect ring closure to give thecyclocarbamate derivative 5. Suitable conditions would involve treatmentof 4 with a base such as potassium hydroxide in a solvent such asethanol or potassium t-butoxide in a solvent such as tetrahydrofuran.The reaction can be carried out in an inert atmosphere (nitrogen orargon) from 0° C. up to the reflux temperature of the solvent.

[0117] Alternatively the carbamate protecting group present in 4 may beremoved under conditions appropriate for its removal to afford 6 (Scheme2). Subsequent ring closure of 6 with a reagent such as phosgene,carbonyldiimidazole or dimethyl carbonate in an appropriate solvent(tetrahydrofuran, dichloromethane, benzene, etc.) also will provideaccess to 5.

[0118] Alternatively, compound 4 may be dehydrated to afford theisopropene derivative 7 (Scheme 3). Suitable conditions for thedehydration would be the use of a reagent such as acetic anhydride,methanesulfonyl chloride, p-toluenesulfonyl chloride or trifluoromethanesulfonyl chloride or anhydride, in a solvent such as pyridine,tetrahydrofuran, dichloromethane or benzene. The reaction can be carriedout under an inert atmosphere (nitrogen or argon) from 0° C. up to thereflux temperature of the solvent and may require the presence of a basesuch as 4-dimethylaminopyridine, triethylamine, pyridine or di-isopropylethylamine. Exposure of 7 to acidic conditions would then afford ringclosure to give 5. Suitable conditions would be the use of an acid suchas p-toluenesulfonic acid, methanesulfonic acid or camphorsulfonic acidin a solvent such as dichloromethane, benzene, toluene ortetrahydrofuran. The reaction can be carried out under an inertatmosphere (nitrogen or argon) from 0° C. up to the reflux temperatureof the solvent.

[0119] An alternative route to 5 is shown in Scheme 4. Treatment of thepreviously described compound 8 (M. Sugiyama, T. Sakamoto, K. Tabata, K.Endo, K. Ito, M. Kobayashi, H. Fukiumi, Chem. Pharm. Bull., 37(8): 2091(1989)) with an organo-metallic reagent such as a Grignard reagent, analkyl or aryl zinc reagent, an alkyl or aryl lithium reagent in an inertsolvent (tetrahydrofuran, diethylether) under an inert atmosphere(nitrogen or argon) at a suitable temperature from 0° C. up to refluxtemperature of the solvent will then provide the tertiary alcohol 9.Compound 9 may then be subjected to basic conditions to effect ringclosure to give the cyclocarbamate derivative 10. Suitable conditionswould involve treatment of 10 with a base such as potassium hydroxide ina solvent such as ethanol or potassium t-butoxide in a solvent such astetrahydrofuran. The reaction can be carried out in an inert atmosphere(nitrogen or argon) from 0° C. up to the reflux temperature of thesolvent. Compound 10 may then be converted to the brominated derivative11. Suitable conditions would be treatment with bromine orN-bromosuccinimide in a solvent such as dichloromethane, tetrahydrofuranor acetic acid. The reaction can be carried out in an inert atmosphere(nitrogen or argon) from 0° C. up to the reflux temperature of thesolvent in the presence of an additive such as silica gel. Subsequentreaction of 11 with an aryl or heteroaryl boronic acid, boronic acidanhydride or trialkyl stannane then provides access to the desiredbiaryl compound 5. The reaction can be carried out in a solvent such asacetone, ethanol, benzene, toluene or tetrahydrofuran, under an inertatmosphere (nitrogen or argon) from 0° C. up to the reflux temperatureof the solvent, in the presence of a palladium catalyst such astetrakis(triphenylphosphine)palladium (0) or palladium acetate and mayrequire an additive such as sodium carbonate, cesium fluoride orpotassium phosphate.

[0120] Alternatively, 10 (Scheme 5) may be treated at low temperaturewith a reagent such as an alkyl lithium or lithium amide in an inertsolvent such as tetrahydrofuran, and then converted to a boronic acid 12(M═B(OH)₂) under the action of trimethyl or triisopropyl borate, or intoa stannane via reaction with trimethyltin chloride or bis(trimethyltin).Subsequent reaction of 12 with an aryl or heteroaryl bromide or iodidein the presence of a palladium catalyst such astetrakis(triphenylphosphine) palladium (0) or palladium acetate and mayrequire an additive such as sodium carbonate, cesium fluoride orpotassium phosphate, would then effect conversion into the desiredthiophene cyclocarbamate 5.

[0121] B. Methods for synthesizing the thiophene cyclocarbamatecompounds depicted in Scheme 6 are described below:

[0122] The amino thiophene compounds 15 (Scheme 6) are preparedaccording to a literature procedure (Comprehensive HeterocyclicChemistry II. A Review of the Literature 1982-1995. A. R. Katrisky etal., Vol. 2, page 639) which involves treating a suitably substitutedaromatic methyl ketone 13 with phosphorus oxychloride in N,N-dimethylformamide to afford the chloro cyano olefin derivative 14. Allowing 14to react with methyl mercaptoacetate in methanol containing sodiummethoxide affords the key aminothiophene carboxylate starting material.Reaction of the 2-amino group with a suitable chloroformate or carbonateaffords the protected amine 16. This can be accomplished by allowing 15to react with a chloroformate or carbonate derivative such as methylchloroformate, ethyl chloroformate, allyl chloroformate,2-(trimethylsilyl)ethyl chloroformate or di-tert-butyldicarbonate in asolvent such as benzene, toluene, xylene, dichloromethane,tetrahydrofuran or pyridine. The reaction can be carried out under aninert atmosphere (nitrogen or argon) from 0° C. up to the refluxtemperature of the solvent and may require the presence of a base suchas 4-dimethylaminopyridine, triethylamine, pyridine or di-isopropylethylamine. Treatment of the protected amino compound 16 with anorgano-metallic reagent such as a Grignard reagent, an alkyl oraryl-zinc reagent, an alkyl or aryl lithium reagent in an inert solvent(tetrahydrofuran, diethylether) under an inert atmosphere (nitrogen orargon) at a suitable temperature from 0° C. up to reflux temperature ofthe solvent will then provide the tertiary alcohol 17. Compound 17 maythen be subjected to basic conditions to effect ring closure to give thecyclocarbamate derivative 18. Suitable conditions would involvetreatment of 4 with a base such as potassium hydroxide in a solvent suchas ethanol or potassium t-butoxide in tetrahydrofuran. The reaction canbe carried out in an inert atmosphere (nitrogen or argon) from 0° C. upto the reflux temperature of the solvent.

[0123] Alternatively the carbamate protecting group present in 17 may beremoved under conditions appropriate for its removal to afford 19(Scheme 7). Subsequent ring closure of 19 with a reagent such asphosgene, carbonyldiimidazole or dimethyl carbonate in an appropriatesolvent (tetrahydrofuran, dichloromethane, benzene, etc.) also willprovide access to 18.

[0124] Alternatively, compound 17 may be dehydrated to afford theisopropene derivative 20 (Scheme 8). Suitable conditions for thedehydration would be the use of a reagent such as acetic anhydride,methanesulfonyl chloride, p-toluenesulfonyl chloride or trifluoromethanesulfonyl chloride or anhydride, in a solvent such as pyridine,tetrahydrofuran, dichloromethane or benzene. The reaction can be carriedout under an inert atmosphere (nitrogen or argon) from 0° C. up to thereflux temperature of the solvent and may require the presence of a basesuch as 4-dimethylaminopyridine, triethylamine, pyridine or di-isopropylethylamine. Exposure of 20 to acidic conditions would then afford ringclosure to give 18. Suitable conditions would be the use of an acid suchas p-toluenesulfonic acid, methanesulfonic acid or camphorsulfonic acidin a solvent such as dichloromethane, benzene, toluene ortetrahydrofuran. The reaction can be carried out under an inertatmosphere (nitrogen or argon) from 0° C. up to the reflux temperatureof the solvent.

[0125] An alternative route to 18 is shown in Scheme 9. Treatment of thepreviously described compound 21, as taught by H. Fukiumi, M. Sugiyama,T. Sakamoto, Chem. Pharm. Bull., 37(5):1197 (1989), with anorgano-metallic reagent such as a Grignard reagent, an alkyl or arylzinc reagent, an alkyl or aryl lithium reagent in an inert solvent(tetrahydrofuran, diethylether) under an inert atmosphere (nitrogen orargon) at a suitable temperature from 0° C. up to reflux temperature ofthe solvent will then provide the tertiary alcohol 22. Compound 22 maythen be subjected to basic conditions to effect ring closure to give thecyclocarbamate derivative 23. Suitable conditions would involvetreatment of 22 with a base such as potassium hydroxide in a solventsuch as ethanol or potassium t-butoxide in tetrahydrofuran. The reactioncan be carried out in an inert atmosphere (nitrogen or argon) from 0° C.up to the reflux temperature of the solvent. Compound 23 may then beconverted to the brominated derivative 24. Suitable conditions would betreatment with bromine or N-bromosuccinimide in a solvent such asdichloromethane, tetrahydrofuran or acetic acid. The reaction can becarried out in an inert atmosphere (nitrogen or argon) from 0° C. up tothe reflux temperature of the solvent in the presence of an additivesuch as silica gel. Subsequent reaction of 24 with an aryl or heteroarylboronic acid boronic acid anhydride or trialkyl stannane then providesaccess to the desired biaryl compound 18. The reaction can be carriedout in a solvent such as acetone, ethanol, benzene, toluene ortetrahydrofuran, under an inert atmosphere (nitrogen or argon) from 0°C. up to the reflux temperature of the solvent, in the presence of apalladium catalyst such as tetrakis(triphenylphosphine)palladium (0) orpalladium acetate and may require an additive such as sodium carbonate,cesium fluoride or potassium phosphate.

[0126] Alternatively, 23 (Scheme 10) may be treated at low temperaturewith a reagent such as an alkyl lithium or lithium amide in an inertsolvent such as tetrahydrofuran, and then converted to a boronic acid 25(M═B(OH)₂) under the action of trimethyl or triisopropyl borate, or intoa stannane via reaction with trimethyltin chloride or bis(trimethyltin).Subsequent reaction of 25 with an aryl or heteroaryl bromide or iodidein the presence of a palladium catalyst such astetrakis(triphenylphosphine) palladium (0) or palladium acetate and mayrequire an additive such as sodium carbonate, cesium fluoride orpotassium phosphate, would then effect conversion into the desiredthiophene cyclocarbamate 18.

[0127] C. Method for synthesizing the thiophene thiocyclocarbamatecompounds 26 and 27 depicted in Scheme 11 are described below:

[0128] Thiophene thiocyclocarbamates 26 and 27 may be obtained directlyby treating 5 and 18 respectively with phosphorus pentasulfide inrefluxing pyridine. Alternatively 5 and 18 may be treated withLawesson's reagent([2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide])in refluxing pyridine to afford 26 and 27, respectively.

[0129] Process for Making Thiazole Cyclocarbamate Derivatives

[0130] Methods for preparing the thiazole cyclocarbamate compounds aredescribed below.

[0131] Thus the thiazole 28 was prepared according to a literatureprocedure, schemel 2 by B. Golankiewicz and P. Januszczyk, Tetrahedron,41:5989 (1985). Reaction of the amine 28 with a suitable chloroformateor carbonate then gives the protected amine 29. This may be accomplishedby reacting compound 28 with a chloroformate or carbonate derivativesuch as methylchloroformate, ethylchloroformate, allylchloroformate,2-(trimethylsilyl)ethylchloroformate or di-tert-butyldicarbonate in asolvent such as dichloromethane, THF, benzene, xylene or pyridine. Thereaction can be carried out under an inert atmosphere (nitrogen orargon) from 0° C. up to the reflux temperature of the solvent and mayrequire the presence of a base such as 4-dimethylaminopyridine,triethylamine, pyridine or di-isopropyl ethylamine. Exposure of compound29 to an organo-metallic reagent such as a Grignard reagent, an alkyl oraryl-zinc reagent, an alkyl or aryl lithium reagent in an inert solvent(THF, diethyl ether) under an inert atmosphere (nitrogen or argon) at asuitable temperature from 0° C. up to the reflux temperature of thesolvent will then provide the alcohol 30. Compound 30 may then beexposed to basic conditions to effect ring closure to give thecyclocarbamate derivative 31. Suitable conditions would involvetreatment of compound 30 with a base such as potassium hydroxide in asolvent such as ethanol. The reaction can be carried out under an inertatmosphere (nitrogen or argon) from 0° C. up to the reflux temperatureof the solvent

[0132] Alternatively the carbamate protecting group present in compound30 may be removed under conditions appropriate for its removal to affordcompound 32 as taught by T. W. Greene and P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, second ed., Wiley-Interscience (1991).Subsequent ring closure of compound 32 with a reagent such as phosgene,carbonyl diimidazole or dimethyl carbonate in an appropriate solvent(THF, dichloromethane, benzene, etc) will also provide access tocompound 31.

[0133] Alternatively, if compound 30 is a tertiary alcohol then it maybe dehydrated to afford the isopropene derivative 33, scheme 3. Suitableconditions for the dehydration would the use of a reagent such as aceticanhydride, methanesulfonyl chloride, p-toluenesulfonyl chloride ortrifluoromethane sulfonyl chloride or anhydride, in a solvent such aspyridine, THF, dichloromethane or benzene. The reaction can be carriedout under an inert atmosphere (nitrogen or argon) from 0° C. up to thereflux temperature of the solvent and may require the presence of a basesuch as 4-dimethylaminopyridine, triethylamine, pyridine or di-isopropylethylamine. Exposure of compound 33 to acidic conditions would thenafford ring closure to give compound 31. Suitable conditions would bethe use of an acid such as p-toluenesulfonic acid, methanesulfonic acidor camphorsulfonic acid in a solvent such as dichloromethane, benzene,toluene or THF and the reaction can be carried out under an inertatmosphere (nitrogen or argon) from 0° C. up to the reflux temperatureof the solvent.

[0134] Compound 31 may then be converted into the bromide 34, scheme 15.Suitable conditions would be exposure to bromine or N-bromosuccinimidein a solvent such as dichloromethane, THF or acetic acid, the reactioncan be carried out under an inert atmosphere (nitrogen or argon) from 0°C. up to the reflux temperature of the solvent in the presence of anadditive such as silica gel. Subsequent reaction of compound 34 with anaryl or heteroaryl boronic acid, boronic acid anhydride or trialkylstannane then provides access to the desired biaryl compound 35. Thereaction can be carried out in a solvent such as acetone, ethanol,benzene, toluene or THF, under an inert atmosphere (nitrogen or argon)from 0° C. up to the reflux temperature of the solvent, in the presenceof a palladium catalyst such as tetrakis(triphenylphosphine) palladium(0) or palladium acetate and may require an additive such as sodiumcarbonate, cesium fluoride or potassium phosphate.

[0135] Alternatively compound 31 may be treated at low temperature witha reagent such as an alkyl lithium or lithium amide in an inert solventsuch as THF, and then converted into a boronic acid (M═B(OH)₂) 36 underthe action of trimethyl or triisopropyl borate, or into a stannane underthe action of trimethyltin chloride or bis(trimethyltin), Scheme 16.Subsequent reaction with an aryl or heteroaryl bromide or iodide in thepresence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium (0) or palladium acetate and may require an additive such assodium carbonate, cesium fluoride or potassium phosphate would theneffect conversion into the desired compound 35.

Amide Derivatives

[0136] Process for Making Amide Thiophene Derivatives

[0137] A method for preparing thiophene derivatives is described below,scheme 17.

[0138] Thus the amine 37 is converted into a carbamate, such as atert-butyl carbamate as described in scheme 1 for the preparation ofcompound 2. Hydrolysis of the ester 38 under basic conditions, forexample lithium or sodium hydroxide in THF or methanol at roomtemperature then gives the acid 39. Conversion of the acid 39 into theacid chloride 40 is accomplished under standard conditions, thionylchloride or oxalyl chloride either neat or in the presence of a solventsuch as dichloromethane and an additive such as a catalytic amount ofN,N-dimethylformamide. Compound 40 is then reacted with diazomethane ortrimethylsilyldiazomethane in an inert solvent such as THF ordichloromethane, and the product diazoketone 41 is then rearranged inthe presence of silver (I) oxide to afford the acid 42. Treatment ofcompound 42 under conditions that specifically remove the protectingcarbamate functionality, for example acidic conditions, will then affectcyclization to give compound 43. Reaction of compound 43 with analkylating agent such as an alkyl iodide, bromide, tosylate or mesylate,or a bis-alkyl iodide, bromide, tosylate or mesylate, under basicconditions, for example butyl lithium in the presence ofN,N,N,N-tetramethylene diamine in a solvent such as THF under an inertatmosphere (nitrogen or argon) at a temperature between −78° C. and theboiling point of the solvent, will then afford the alkylated 44.

[0139] Process for Making Thiazole Derivatives

[0140] A method for preparing thiazole derivatives is described below,scheme 18.

[0141] Hydrolysis of the ester 29 under basic conditions, for examplelithium or sodium hydroxide in THF or methanol at room temperature thengives the acid 45. Conversion of the acid 45 into the acid chloride 46is accomplished under standard conditions, for example thionyl chlorideor oxalyl chloride either neat or in the presence of a solvent such asdichloromethane and an additive such as a catalytic amount ofN,N-dimethylformamide. Compound 46 is then reacted with diazomethane ortrimethylsilyldiazomethane in an inert solvent such as THF ordichloromethane, and the product diazoketone 47 is then rearranged inthe presence of silver (I) oxide to afford the acid 48. Treatment ofcompound 48 under conditions that specifically remove the protectingcarbamate functionality, for example acidic conditions, will then affectcyclization to give the heterocycle 49. Reaction of compound 49 with analkylating agent such as an alkyl iodide, bromide, tosylate or mesylate,or a bis-alkyl iodide, bromide, tosylate or mesylate, under basicconditions, for example butyl lithium in the presence ofN,N,N,N-tetramethylene diamine in a solvent such as THF under an inertatmosphere (nitrogen or argon) at a temperature between −78° C. and theboiling point of the solvent, will then afford the alkylated heterocycle50. Compound 50 may then be converted into the bromide 51. Suitableconditions would be exposure to bromine or N-bromosuccinimide in asolvent such as dichloromethane, THF or acetic acid, the reaction can becarried out under an inert atmosphere (nitrogen or argon) from 0° C. upto the reflux temperature of the solvent in the presence of an additivesuch as silica gel. Subsequent reaction of compound 51 with an aryl orheteroaryl boronic acid, boronic acid anhydride or trialkyl stannanethen provides access to the desired biaryl compound 52. The reaction canbe carried out in a solvent such as acetone, ethanol, benzene, tolueneor THF, under an inert atmosphere (nitrogen or argon) from 0° C. up tothe reflux temperature of the solvent, in the presence of a palladiumcatalyst such as tetrakis(triphenylphosphine) palladium (0) or palladiumacetate and may require an additive such as sodium carbonate, cesiumfluoride or potassium phosphate. The thione derivative, compound 53, maybe obtained directly by treating 52 with phosphorus pentasulfide inrefluxing pyridine. Alternatively 52 may be treated with Lawesson'sreagent in refluxing pyridine to afford 53.

[0142] The compounds of the present invention can be used in the form ofsalts derived from pharmaceutically or physiologically acceptable acidsor bases. These salts include, but are not limited to, the followingsalts with inorganic acids such as hydrochloric acid, sulfuric acid,nitric acid, phosphoric acid and, as the case may be, such organic acidsas acetic acid, oxalic acid, succinic acid, and maleic acid. Other saltsinclude salts with alkali metals or alkaline earth metals, such assodium, potassium, calcium or magnesium in the form of esters,carbamates and other conventional “pro-drug” forms, which, whenadministered in such form, convert to the active moiety in vivo.

[0143] This invention includes pharmaceutical compositions andtreatments which comprise administering to a mammal a pharmaceuticallyeffective amount of one or more compounds as described above wherein Qis oxygen as antagonists of the progesterone receptor. The inventionfurther provides comparable methods and compositions which utilize oneor more compounds herein wherein Q is S, NR⁶, or CR⁷R⁸ as agonists ofthe progesterone receptor.

[0144] The progesterone receptor antagonists of this invention, usedalone or in combination, can be utilized in methods of contraception andthe treatment and/or prevention of benign and malignant neoplasticdisease. Specific uses of the compounds and pharmaceutical compositionsof invention include the treatment and/or prevention of uterinemyometrial fibroids, endometriosis, benign prostatic hypertrophy;carcinomas and adenocarcinomas of the endometrium, ovary, breast, colon,prostate, pituitary, meningioma and other hormone-dependent tumors.Additional uses of the present progesterone receptor antagonists includethe synchronization of the estrus in livestock.

[0145] The progesterone receptor agonists of this invention, used aloneor in combination, can be utilized in methods of contraception and thetreatment and/or prevention of dysfunctional bleeding, uterineleiomyomata, endometriosis; polycystic ovary syndrome, carcinomas andadenocarcinomas of the endometrium, ovary, breast, colon, prostate.Additional uses of the invention include stimulation of food intake.

[0146] This invention also includes pharmaceutical compositionscomprising one or more compounds of this invention with apharmaceutically acceptable carrier or excipient. When the compounds areemployed for the above utilities, they may be combined with one or morepharmaceutically acceptable carriers or excipients, for example,solvents, diluents and the like, and may be administered orally in suchforms as tablets, capsules, dispersible powders, granules, orsuspensions containing, for example, from about 0.05 to 5% of suspendingagent, syrups containing, for example, from about 10 to 50% of sugar,and elixirs containing, for example, from about 20 to 50% ethanol, andthe like, or parenterally in the form of sterile injectable solutions orsuspensions containing from about 0.05 to 5% suspending agent in anisotonic medium. Such pharmaceutical preparations may contain, forexample, from about 25 to about 90% of the active ingredient incombination with the carrier, more usually between about 5% and 60% byweight.

[0147] The effective dosage of active ingredient employed may varydepending on the particular compound employed, the mode ofadministration and the severity of the condition being treated. However,in general, satisfactory results are obtained when the compounds of theinvention are administered at a daily dosage of from about 0.5 to about500 mg/kg of animal body weight, preferably given in divided doses twoto four times a day, or in a sustained release form. For most largemammals, the total daily dosage is from about 1 to 100 mg, preferablyfrom about 2 to 80 mg. Dosage forms suitable for internal use comprisefrom about 0.5 to 500 mg of the active compound in intimate admixturewith a solid or liquid pharmaceutically acceptable carrier. This dosageregimen may be adjusted to provide the optimal therapeutic response. Forexample, several divided doses may be administered daily or the dose maybe proportionally reduced as indicated by the exigencies of thetherapeutic situation.

[0148] These active compounds may be administered orally as well as byintravenous, intramuscular, or subcutaneous routes. Solid carriersinclude starch, lactose, dicalcium phosphate, microcrystallinecellulose, sucrose and kaolin, while liquid carriers include sterilewater, polyethylene glycols, non-ionic surfactants and edible oils suchas corn, peanut and sesame oils, as are appropriate to the nature of theactive ingredient and the particular form of administration desired.Adjuvents customarily employed in the preparation of pharmaceuticalcompositions may be advantageously included, such as flavoring agents,coloring agents, preserving agents, and antioxidants, for example,vitamin E, ascorbic acid, BHT and BHA.

[0149] The preferred pharmaceutical compositions from the standpoint ofease of preparation and administration are solid compositions,particularly tablets and hard-filled or liquid-filled capsules. Oraladministration of the compounds is preferred.

[0150] These active compounds may also be administered parenterally orintraperitoneally. Solutions or suspensions of these active compounds asa free base or pharmacologically acceptable salt can be prepared inwater suitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid, polyethyleneglycols and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

[0151] The pharmaceutical forms suitable for injectable use includesterile aqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringe ability exits. It must be stable underconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacterial and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol (e.g., glycerol, propylene glycol and liquid polyethyleneglycol), suitable mixtures thereof, and vegetable oil.

[0152] The following non-limiting examples are illustrative of exemplarycompound 5.

EXAMPLE 16-(3-chlorophenyl)-1,4-dihydro-4,4-dimethyl-2H-thieno[2,3-d][1,3]oxazine-2-one2-(3-Chlorobenzyl)acetaldehyde

[0153] To a 25° C. solution of 3-chlorostyrene in anhydrous CH₂Cl₂ (10.0g, 72.15 mmol) was added a well-stirred solution of Pb(OAc)₄ (35.2 g,79.4 mmol) in trifluoroacetic acid (150 mL), dropwise. The reaction wascompleted within 30 min of the addition and after being stirred for afurther 30 min, the mixture was poured into water, extracted with ether(3×), the combined organic layers were washed with saturated NaHCO₃solution, water, dried (MgSO₄), and concentrated to a volume of about 15ml and immediately used for the following reaction described below.

2-Amino-5-(3-chloro-phenyl)-thiophene-3-carboxylic acid methyl ester

[0154] To the crude aldehyde, prepared above, in methanol was added amixture of sulfur (2.55 g, 79.44 mmol), methylcyanoacetate (7.88 g,79.44 mmol), morpholine (6.92 g, 79.44) and the resulting reactionmixture was refluxed for 16 hours. The unreacted sulfur was filtered offand the filtrates were evaporated leaving behind a black residue. Thisresidue was extracted with ether and washed with H₂O. Crystallized fromether/hexane (1:5) to obtain white crystals (3.85 g, 14.3 mmol, 50%), mp85-87°. ¹HNMR (DMSO-d₆) δ3.75 (s, 3H), 7.18-7.27 (m, 1H), 7.31-7.42 (m,3H), 7.53 (s, 1H), 7.62 (s, 1H); MS(+APCI) m/z268(M+H); Anal. Calc. ForC₁₂H₁₀ClNO₂S: C, 53.83, H, 3.76, N, 5.23. Found: C, 53.57, H, 3.37, N,5.00.

2-Allyloxycarbonylamino-5-(3-chloro-phenyl)-thiophene-3-carboxylic acidmethyl ester

[0155] To a solution of2-amino-5-(3-chloro-phenyl)-thiophene-3-carboxylic acid methyl ester (2g, 7.5 mmol) in anhydrous 1,2-dichloroethane (50 mL) was added at roomtemperature under nitrogen allyl chloroformate (1.6 mL, 15.1 mmol). Thereaction mixture was heated at reflux under nitrogen for 18 hours,cooled to room temperature, and treated with a saturated aqueous sodiumbicarbonate solution (100 mL). The organic layer was separated andaqueous layer was extracted with methylene chloride (3×20 mL). Thecombined organic layers were washed (brine) and dried (MgSO₄). Afterremoval of the solvent, the residue was purified by a flash silica gelcolumn (hexane:ethyl acetate/7:1) to give the subtitled compound as anoff-white solid (2.14 g, 81%): ¹H-NMR (DMSO-d₆) δ10.2 (s, 1H), 7.73 (t,1H, J=1.7 Hz), 7.66 (s, 1H), 7.57 (dt, 1H, J=7.7, 1.7 Hz), 7.41 (t, 1H,J=7.7 Hz), 7.34 (dt, 1H, J=6.8, 1.6 Hz), 6.01 (m, 1H), 5.41 (dd, 1H,J=7.3, 1.6 Hz), 5.29 (dd, 1H, J=10.5, 1.3 Hz), 4.74 (d, 2H, J=5.5 Hz),3.84 (s, 3H). Anal. Calc. For C₁₆H₁₄ClNO₄S: C, 54.63, H, 4.01, N, 3.98.Found: C, 54.56, H, 3.92, N, 3.89.

[0156] To a solution of2-allenoxycarbonylamino-5-(3-chloro-phenyl)-thiophene-3-carboxylic acidmethyl ester (0.1 g, 0.28 mmol) in anhydrous THF was added a solution ofmethylmagnesium bromide (3.0 M in diethyl ether, 1.5 mL, 4.5 mmol) atroom temperature under nitrogen. After stirring at room temperatureunder nitrogen for 20 minutes, the reaction mixture was treated withbrine (10 mL) followed by addition of an aqueous 1N HCl solution (5 mL).Ethyl acetate (20 mL) was added and organic layer was separated, washed1N with brine (5 mL) and dried over MgSO₄. After removal of the solvent,the residue was purified by a flash column (silica gel, hexane:ethylacetate/5:1) to give carbinol which was used in next step withoutfurther purification and characterization.

[0157] A mixture of above crude carbinol, potassium hydroxide (excess)in ethanol was stirred at room temperature under nitrogen overnight. Thereaction solution was then acidified by an addition of a cold aqueous 1NHCl solution. Ethyl acetate (20 mL) was added and organic layer wasseparated, washed with brine (5 mL) and dried (MgSO₄). After removal ofthe solvent, the residue was purified by a silica gel column(hexane:ethyl acetate/2:1) to give the title compound as an off-whitesolid (16 mg, 19% for two steps): mp 149-150° C.; ¹H-NMR (DMSO-d₆)δ10.69 (s, 1H), 7.64 (t, 1H, J=1.8 Hz), 7.49 (s, 1H), 7.47 (dt, 1H,J=7.7, 1.4 Hz), 7.39 (t, 1H, J=7.8 Hz), 7.29 (dt, 1H, J=7.8, 1.3 Hz),1.61 (s, 6H). MS (EI) m/z 293/295 (M⁺). Anal. Calc. For C₁₄H₁₂ClNO₂S: C,57.24, H, 4.12, N, 4.77. Found: C, 57.27, H, 4.25, N, 4.66.

EXAMPLE 2

[0158]6-(3-chlorophenyl)-1,4-dihydro-4,4-dimethyl-2H-thieno[3,2-d][1,3]oxazine-2-one3-Chloro-3-(3-chloro-phenyl)-acrylonitrile

[0159] A solution of POCl₃ was slowly added to anhydrous DMF over aperiod of 20 minutes and the temperature was maintained around 30° C.3′-Chloroacetophenone solution in anhydrous DMF was added to the abovesolution and the reaction temperature was allowed to rise to around 50°C. Hydroxylamine HCl was added to the reaction solution, portionwise,over 1 hour. A volume of 500 mL of water was added to form precipitate,stirred for 1 hour and precipitate was collected on a Büchner funnel,washed with H₂O, and dried to afford a yellow crystalline compound, mp60-62° C. ¹H NMR (DMSO-d₆) δ1.60(s, 6H), 7.30 (d, 1H, J=8.41 Hz),7.41(d, 1H, J=8.41 Hz), 10.47 (s, 1H); MS(+APCI)m/z 213(M+H); Anal.Calc. For C₉H₉ClN₂O₂: C, 50.84, H, 4.27, N, 13.17. Found: C, 50.99, H,4.28, N, 12.98.

3-Amino-5-(3-chloro-phenyl)-thiophene-2-carboxylic acid methyl ester

[0160] Sodium pellets were slowly added to methanol solution to formNaOMe in situ, then methyl thioglycolate was added over a period of 20minutes to the methanol solution. A solution of3-Chloro-3-(3-chloro-phenyl)-acrylonitrile in methanol was added slowlyand was brought to reflux for 1 hour. The reaction mixture was cooled toroom temperature and methanol was concentrated to 100 mL and 200 mL ofwater was added, stirred for 30 minutes and the yellow precipitate wascollected and washed with water several times to yield a yellowcrystalline compound, mp 92-95° C. ¹H NMR (DMSO-d₆) δ1.60 (s, 6H), 7.30(d, 1H, J=8.41 Hz), 7.41(d, 1H, J=8.41 Hz), 10.47 (s, 1H); MS(+APCI)m/z213(M+H); Anal. Calc. For C₉H₉ClN₂O₂: C, 50.84, H, 4.27, N, 13.17.Found: C, 50.99, H, 4.28, N, 12.98.

3-Allyloxycarbonylamino-5-(3-chloro-phenyl)-thiophene-2-carboxylic acidmethyl ester

[0161] To a solution of3-Amino-5-(3-chloro-phenyl)-thiophene-2-carboxylic acid methyl ester (51g, 56.0 mmol) in toluene (200 mL) was added a solution of allylchloroformate (8.10 g, 67.2 mmol) in toluene (5.0 mL) and the resultingreaction solution was heated under reflux for 3 h. Toluene was strippeddown and the crystals were collected and washed with ether/hexane toafford a yellow crystalline compound, mp 101-103° C. ¹H NMR (DMSO-d₆)δ3.85 (s,3H), 4.68-4.71 (d, 2H, J=5.46 Hz), 5.26-5.30 (dd, 1H, J=1.35,9.84 Hz), 5.36-5.42 (dd, 1H, J=1.57, 15.68 Hz), 5.96(m, 2H), 7.50-7.52(m, 2H), 7.67-7.71 (m, 1H), 7.79 (s, 1H), 8.10 (s, 1H); MS(+APCI) m/z352(M+H); Anal. Calc. For C₁₆H₁₄ClNO₄S: C, 54.63, H, 4.01, N, 3.97.Found: C, 54.05, H, 4.17, N, 3.84.

[5-(3-Chloro-phenyl)-2-(1-hydroxy-1-methyl-ethyl)-thiophen-3-yl]-carbamicacid allyl ester

[0162] To a solution of3-Allyloxycarbonylamino-5-(3-chloro-phenyl)-thiophene-2-carboxylic acidmethyl ester (5.3 g, 15.1 mmol) in anhydrous THF (30 mL) at roomtemperature was added a solution of 3.0M MeMgI in ether (20.1 mL, 60.24mmol). After 30 minutes, the reaction was slowly quenched with H₂O (10mL), treated with saturated NH₄OH (100 mL), extracted with ether (200mL), washed with brine, dried (MgSO₄), concentrated, and chromatographed(hexane/ether, 1:4): mp 60-61° C.; ¹H NMR (DMSO-d₆) δ1.52 (s, 6H),4.59-4.61 (d, 2H, J=5.35 Hz), 5.22-5.36 (m, 2H), 5.91-6.04 (m, 2H),7.33-7.67 (m, 5H), 8.89 (s, 1H); MS(EI) m/z 351/353(M+H); Anal. Calc.For C₁₇H₁₈ClNO₃S: C, 58.03, H, 5.16, N, 3.98. Found: C, 58.17, H, 5.16,N, 3.97.

6-(3-Chlorophenyl)-1,4-dihydro-4,4-dimethyl-2H-thieno[3,2-d][1,3]oxazin-2-one

[0163] To a solution of[5-(3-Chloro-phenyl)-2-(1-hydroxy-1-methyl-ethyl)-thiophen-3-yl]-carbamicacid allyl ester (0.12 g, 0.34 mmol) in anhydrous THF (5.0 mL) was addedKO^(t)Bu (0.076 g, 0.068 mmol) and stirred for 15 minutes, quenched withH₂O, and in situ crystallization was carried out by adding minimalamount of MeOH to the solution. The white crystals were collected on aBüchner funnel, mp 123-125° C. ¹H NMR (DMSO-d₆) δ1.64(s, 6H), 7.05(s,1H), 7.37-7.48(m, 2H), 7.53-7.56(s, 1H), 7.67-7.68 (m,1H), 10.41(s, 1H);MS(EI) m/z 293/295(M+H); Anal. Calc. For C₁₇H₁₈ClNO₃S: C, 57.24, H,4.12, N, 4.77. Found: C, 56.93, H, 3.92, N, 4.97.

EXAMPLE 3 Pharmacology

[0164] The progestational activity of the current invention wasevaluated in the PRE-luciferase assay in CV-1 cells, described below.In-vitro potencies can be in the range 0.01 nM-10,000 nM. In vivopotencies are anticipated to be in the range 1 mg/kg to 30 mg/kg.

[0165] The object of this assay is to determine a compound'sprogestational or antiprogestational potency based on its effect onPRE-luciferase reporter activity in CV-1 cells co-transfected with humanPR and PRE-luciferase plasmids. The materials methods used in the assayare as follows.

[0166] a. Medium

[0167] The growth medium was as follows: DMEM (BioWhittaker) containing10% (v/v) fetal bovine serum (heat inactivated), 0.1 mM MEMnon-essential amino acids, 100 U/ml penicillin, 100 mg/ml streptomycin,and 2 mM GlutaMax (GIBCO, BRL). The experimental medium was as follows:DMEM (BioWhittaker), phenol red-free, containing 10% (v/v)charcoal-stripped fetal bovine serum (heat-inactivated), 0.1 mM MEMnon-essential amino acids, 100 U/ml penicillin, 100 mg/ml streptomycin,and 2 mM GlutaMax (GIBCO, BRL).

[0168] b. Cell Culture, Transfection, Treatment, and Luciferase Assay

[0169] Stock CV-1 cells are maintained in growth medium. Co-transfectionis done using 1.2×10⁷ cells, 5 mg pLEM plasmid with hPR-B inserted atSph1 and BamH1 sites, 10 mg pGL3 plasmid with two PREs upstream of theluciferase sequence, and 50 mg sonicated calf thymus DNA as carrier DNAin 250 ml. Electroporation is carried out at 260 V and 1,000 mF in aBiorad Gene Pulser II. After electroporation, cells are resuspended ingrowth medium and plated in 96-well plate at 40,000 cells/well in 200μl. Following overnight incubation, the medium is changed toexperimental medium. Cells are then treated with reference or testcompounds in experimental medium. Compounds are tested forantiprogestational activity in the presence of 3 nM progesterone.Twenty-four hr. after treatment, the medium is discarded, cells arewashed three times with D-PBS (GIBCO, BRL). Fifty μl of cell lysisbuffer (Promega, Madison, Wis.) is added to each well and the plates areshaken for 15 min in a Titer Plate Shaker (Lab Line Instrument, Inc.).Luciferase activity is measured using luciferase reagents from Promega.

[0170] c. Analysis of Results

[0171] Each treatment consists of at least 4 replicates. Log transformeddata are used for analysis of variance and nonlinear dose response curvefitting for both agonist and antagonist modes. Huber weighting is usedto downweight the effects of outliers. EC₅₀ or IC₅₀ values arecalculated from the retransformed values. JMP software (SAS Institute,Inc.) is used for both one-way analysis of variance and non-linearresponse analyses.

[0172] d. Reference Compounds

[0173] Progesterone and trimegestone are reference pro gestins and RU486is the reference antiprogestin. All reference compounds are run in fulldose-response curves and the EC₅₀ or IC₅₀ values are calculated. TABLE 1Estimated EC₅₀, standard error (SE), and 95% confidence intervals (CI)for reference progestins from three individual studies EC50 95% CICompound Exp. (nM) SE lower upper Progesterone 1 0.616 0.026 0.509 0.7462 0.402 0.019 0.323 0.501 3 0.486 0.028 0.371 0.637 Trimegestone 10.0075 0.0002 0.0066 0.0085 2 0.0081 0.0003 0.0070 0.0094 3 0.00670.0003 0.0055 0.0082

[0174] TABLE 2 Estimated IC₅₀, standard error (SE), and 95% confidentinterval (CI) for the antiprogestin, RU486 from three individual studiesIC 50 95% CI Compound Exp. (nM) SE lower upper RU486 1 0.028 0.002 0.0190.042 2 0.037 0.002 0.029 0.048 3 0.019 0.001 0.013 0.027

[0175] Progestational activity: Compounds that increase PRE-luciferaseactivity significantly (p<0.05) compared to vehicle control areconsidered active.

[0176] Antiprogestational activity: Compounds that decrease 3 nMprogesterone induced PRE-luciferase activity significantly (p<0.05)

[0177] EC₅₀: Concentration of a compound that gives half-maximalincrease PRE-luciferase activity (default-nM) with SE.

[0178] IC₅₀: Concentration of a compound that gives half-maximaldecrease in 3 nM progesterone induced PRE-luciferase activity(default-nM) with SE.

[0179] All publications cited in this specification are incorporatedherein by reference herein. While the invention has been described withreference to a particularly preferred embodiment, it will be appreciatedthat modifications can be made without departing from the spirit of theinvention. Such modifications are intended to fall within the scope ofthe appended claims.

What is claimed:
 1. A compound of Formula I:

wherein: A and B are independent substituents selected from S, CH or N;Provided that when A is S, B is CH or N; provided that when B is S, A isCH or N; and A and B cannot both be CH; and when A and B both equal N,one N may be optionally substituted with an C₁ to C₆ alkyl group; R₁ andR₂ are independent substituents selected from the group of H, C₁ to C₆alkyl, substituted C₁ to C₆ alkyl, C₂ to C₆ alkenyl, substituted C₂ toC₆ alkenyl, C₂ to C₆ alkynyl, substituted C₂ to C₆ alkynyl, C₃ to C₈cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl,heterocyclic, substituted heterocyclic, COR^(A), or NR^(B)COR^(A); or R¹and R² are fused to form: a) an optionally substituted 3 to 8 memberedspirocyclic alkyl ring; or b) an optionally substituted 3 to 8 memberedspirocyclic alkenyl ring; or c) an optionally substituted 3 to 8membered spirocyclic ring containing one to three heteroatoms selectedfrom the group of O, S and N; R^(A) is H, C₁ to C₃ alkyl, substituted C₁to C₃ alkyl, aryl, substituted aryl, C₁ to C₃ alkoxy, substituted C₁ toC₃ alkoxy, C₁ to C₃ aminoalkyl, or substituted C₁ to C₃ aminoalkyl;R^(B) is H, C₁ to C₃ alkyl, or substituted C₁ to C₃ alkyl; R³ is H, OH,NH₂, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₆ alkenyl,substituted C₁ to C₆ alkenyl, alkynyl, or substituted alkynyl, orCOR^(C); R^(C) is H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl,substituted aryl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, or substituted C₁ to C₃ aminoalkyl; R⁴ is a trisubstitutedbenzene ring containing the substituents X, Y and Z as shown below,

X is selected from halogen, CN, C₁ to C₃ alkyl, substituted C₁ to C₃alkyl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃ thioalkyl,substituted C₁ to C₃ thioalkyl, C₁ to C₃ aminoalkyl, substituted C₁ toC₃ aminoalkyl, NO₂, C₁ to C₃ perfluoroalkyl, 5 or 6 memberedheterocyclic ring containing 1 to 3 heteroatoms, COR^(D), OCOR^(D), orNR^(E)COR^(D); R^(D) is H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl,aryl, substituted aryl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁to C₃ aminoalkyl, or substituted C₁ to C₃ aminoalkyl; R^(E) is H, C₁ toC₃ alkyl, or substituted C₁ to C₃ alkyl; Y and Z are independentlyselected from H, halogen, CN, NO₂, C₁ to C₃ alkoxy, C₁ to C₃ alkyl, orC₁ to C₃ thioalkyl; or R⁴ is a five or six membered ring with 1, 2, or 3heteroatoms selected from O, S, SO, SO₂ or NR⁵, the five or six memberedrings being optionally substituted by one or two independentsubstituents selected from H, halogen, CN, NO₂ and C₁ to C₃ alkyl, C₁ toC₃ alkoxy, C₁ to C₃ aminoalkyl, COR^(F), or NR^(G)COR^(F); R^(F) is H,C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl, substituted aryl, C₁to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, orsubstituted C₁ to C₃ aminoalkyl; R^(G) is H, C₁ to C₃ alkyl, orsubstituted C₁ to C₃ alkyl; R⁵ is H, or C₁ to C₃ alkyl; Q is O, S, NR⁶,or CR⁷R⁸; R⁶ is from the group including CN, C₁ to C₆ alkyl, substitutedC₁ to C₆ alkyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl,aryl, substituted aryl, heterocyclic, substituted heterocyclic, orSO₂CF₃; R⁷ and R⁸ are independent substituents from the group includingH, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₈ cycloalkyl,substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocyclic,substituted heterocyclic, NO₂, or CN CO₂R⁹; R⁹ is C₁ to C₃ alkyl; orCR⁷R⁸ may comprise a six membered ring of the structure below:

W is O or a chemical bond or a pharmaceutically acceptable salt thereof.2. A compound of claim 1 wherein: A and B are independent substituentsS, CH or N, provided that when A is S, B is CH or N; and when B is S, Ais CH or N; and A and B cannot both be CH; and when A and B both equalN, one N may be optionally substituted with an C₁ to C₆ alkyl group; R¹is H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₈ cycloalkyl,substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocyclic,substituted heterocyclic, COR^(A), or NR^(B)COR^(A); R² is H, C₁ to C₆alkyl, substituted C₁ to C₆ alkyl, C₂ to C₆ alkenyl, substituted C₂ toC₆ alkenyl, C₂ to C₆ alkynyl, substituted C₂ to C₆ alkynyl, C₃ to C₈cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substituted aryl,heterocyclic, substituted heterocyclic, COR^(A), or NR^(B)COR^(A); or R¹and R² are fused to form: a) an optionally substituted 3 to 8 memberedspirocyclic alkyl ring, or b) an optionally substituted 3 to 8 memberedspirocyclic alkenyl ring; or c) an optionally substituted 3 to 8membered spirocyclic ring containing one to three heteroatoms selectedfrom the group of O, S and N; R^(A) is H, C₁ to C₃ alkyl, substituted C₁to C₃ alkyl, aryl, substituted aryl, C₁ to C₃ alkoxy, substituted C₁ toC₃ alkoxy, C₁ to C₃ aminoalkyl, or substituted C₁ to C₃ aminoalkyl;R^(B) is H, C₁ to C₃ alkyl, or substituted C₁ to C₃ alkyl; R³ is H, OH,NH₂, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₆ alkenyl,substituted C₁ to C₆ alkenyl, alkynyl, or substituted alkynyl, orCOR^(C); R^(C) is H, C₁ to C₄ alkyl, substituted C₁ to C₄ alkyl, aryl,substituted aryl, C₁ to C₄ alkoxy, substituted C₁ to C₄ alkoxy, C₁ to C₄aminoalkyl, or substituted C₁ to C₄ aminoalkyl; R⁴ is a trisubstitutedbenzene ring containing the substituents X, Y and Z as shown below:

X is taken from the group including halogen, CN, C₁ to C₃ alkyl,substituted C₁ to C₃ alkyl, C₁ to C₃ alkoxy, substituted C₁ to C₃alkoxy, C₁ to C₃ thioalkyl, substituted C₁ to C₃ thioalkyl, C₁ to C₃aminoalkyl, substituted C₁ to C₃ aminoalkyl, NO₂, C₁ to C₃perfluoroalkyl, 5-membered heterocyclic ring containing 1 to 3heteroatoms, COR^(D), OCOR^(D), or NR^(E)COR^(D); R^(D) is H, C₁ to C₃alkyl, substituted C₁ to C₃ alkyl, aryl, substituted aryl, C₁ to C₃alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃ aminoalkyl, or substitutedC₁ to C₃ aminoalkyl; R^(E) is H, C₁ to C₃ alkyl, or substituted C₁ to C₃alkyl; Y and Z are independent substituents taken from the groupincluding H, halogen, CN, NO₂, C₁ to C₃ alkoxy, C₁ to C₃ alkyl, or C₁ toC₃ thioalkyl; or R⁴ is a five or six membered ring with 1, 2, or 3heteroatoms selected from O, S, SO, SO₂ or NR⁵, the five or six memberedring being optionally substituted by one or two independent substituentsselected from H, halogen, CN, NO₂ and C₁ to C₃ alkyl, or C₁ to C₃alkoxy; R⁵ is H or C₁ to C₃ alkyl; Q is O, S, NR⁶, or CR⁷R⁸; R⁶ is fromthe group including CN, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₃to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl, substitutedaryl, heterocyclic, substituted heterocyclic, or SO₂CF₃; R⁷ and R⁸ areindependent substituents from the group including H, C₁ to C₆ alkyl,substituted C₁ to C₆ alkyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈cycloalkyl, aryl, substituted aryl, heterocyclic, substitutedheterocyclic, NO₂, or CN CO₂R⁹; R⁹ is C₁ to C₃ alkyl; or CR⁸R⁹ comprisea six membered ring as shown by the structure below

W is O or a chemical bond or a pharmaceutically acceptable salt thereof.3. A compound of claim 1 wherein: A and B are independent substituentsfrom the group including S, CH or N; provided that when A is S, B is CHor N; and when B is S, A is CH or N; and A and B cannot both be CH;R¹═R² and are selected from the group which includes C₁ to C₃ alkyl,substituted C₁ to C₃ alkyl, or spirocyclic alkyl constructed by fusingR¹ and R² to form a 3 to 6 membered spirocyclic ring; R³ is H, OH, NH₂,C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, or COR^(C); R^(C) is H, C₁to C₄ alkyl, or C₁ to C₄ alkoxy; R⁴ is a disubstituted benzene ringcontaining the substituents X and Y as shown below:

X is selected from the group including halogen, CN, C₁ to C₃ alkoxy, C₁to C₃ alkyl, NO₂, C₁ to C₃ perfluoroalkyl, 5 membered heterocyclic ringcontaining 1 to 3 heteroatoms, or C₁ to C₃ thioalkyl; Y is a substituenton the 4′ or 5′ position selected from the group of H, halogen, CN, NO₂,C₁ to C₃ alkoxy, C₁ to C₄ alkyl, or C₁ to C₃ thioalkyl; or R⁴ is a fivemembered ring with the structure shown below:

U is O, S, or NR⁵; R⁵ is H or C₁ to C₃ alkyl, or C₁ to C₄ CO₂alkyl; X′is selected from halogen, CN, NO₂, C₁ to C₃ alkyl or C₁ to C₃ alkoxy; Y′is H or C₁ to C₄ alkyl; or R⁴ is a six membered ring with the structure:

X¹ is N or CX², X² is halogen, CN or NO₂; Q is O, S, NR⁶, or CR⁷R⁸; R⁶is selected from the group including CN, C₁ to C₆ alkyl, substituted C₁to C₆ alkyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl,substituted aryl, heterocyclic, substituted heterocyclic, or SO₂CF₃; R⁷and R⁸ are independent substituents selected from the group of H, C₁ toC₆ alkyl, substituted C₁ to C₆ alkyl, C₃ to C₈ cycloalkyl, substitutedC₃ to C₈ cycloalkyl, aryl, substituted aryl, heterocyclic, substitutedheterocyclic, NO₂, or CN CO₂R⁹; R⁹ is C₁ to C₃ alkyl; or CR⁷R⁸ comprisea six membered ring of the structure:

W is O or a chemical bond; or a pharmaceutically acceptable saltthereof.
 4. A compound of claim 3 wherein: R¹═R² and are selected fromthe group which includes C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, orspirocyclic alkyl constructed by fusing R¹ and R² to form a 3 to 6membered spirocyclic ring; and A, B, R³, R^(C), R⁴, X, Y, U, R⁵, X′, Y′,X¹, X², Q, R⁶, R⁷, R⁸, R⁹ and W are as defined in claim 3; or apharmaceutically acceptable salt thereof.
 5. A compound of claim 3wherein: R¹ and R² are fused to form a 3 to 6 membered spirocyclic ring;and A, B, R³, R^(C), R⁴, X, Y, U, R⁵, X′, Y′, X¹, X², Q, R⁶, R⁷, R⁸, R⁹and W are as or a pharmaceutically acceptable salt thereof.
 6. Acompound of the formula:

wherein: R₁ and R₂ are independent substituents selected from the groupof H, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₂ to C₆ alkenyl,substituted C₂ to C₆ alkenyl, C₂ to C₆ alkynyl, substituted C₂ to C₆alkynyl, C₃ to C₈ cycloalkyl, substituted C₃ to C₈ cycloalkyl, aryl,substituted aryl, heterocyclic, substituted heterocyclic, COR^(A), orNR^(B)COR^(A); or R¹ and R² are fused to form: a) a 3 to 6 memberedspirocyclic alkyl ring; or b) a 3 to 6 membered spirocyclic alkenylring; R³ is H, OH, NH₂, C₁ to C₆ alkyl, substituted C₁ to C₆ alkyl, C₃to C₆ alkenyl, substituted C₁ to C₆ alkenyl, alkynyl, or substitutedalkynyl, or COR^(C); R^(B) is H, C₁ to C₃ alkyl, or substituted C₁ to C₃alkyl; R^(C) is H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl, aryl,substituted aryl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃aminoalkyl, or substituted C₁ to C₃ aminoalkyl; R⁴ is a trisubstitutedbenzene ring containing the substituents X, Y and Z as shown below,

X is selected from halogen, CN, C₁ to C₃ alkyl, substituted C₁ to C₃alkyl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁ to C₃ thioalkyl,substituted C₁ to C₃ thioalkyl, C₁ to C₃ aminoalkyl, substituted C₁ toC₃ aminoalkyl, NO₂, C₁ to C₃ perfluoroalkyl, 5 or 6 memberedheterocyclic ring containing 1 to 3 heteroatoms, COR^(D), OCOR^(D), orNR^(E)COR^(D); R^(D) is H, C₁ to C₃ alkyl, substituted C₁ to C₃ alkyl,aryl, substituted aryl, C₁ to C₃ alkoxy, substituted C₁ to C₃ alkoxy, C₁to C₃ aminoalkyl, or substituted C₁ to C₃ aminoalkyl; R^(E) is H, C₁ toC₃ alkyl, or substituted C₁ to C₃ alkyl; and Y and Z are independentlyselected from H, halogen, CN, NO₂, C₁ to C₃ alkoxy, C₁ to C₃ alkyl, orC₁ to C₃ thioalkyl; or a pharmaceutically acceptable salt thereof.
 7. Acompound of claim 1 which is6-(3-chlorophenyl)-1,4-dihydro-4,4-dimethyl-2H-thieno[2,3-d][1,3]oxazine-2-one,or a pharmaceutically acceptable salt thereof.
 8. A method of inducingcontraception in a mammal, the method comprising administering to amammal in need thereof a compound of claim 1, or a pharmaceuticallyacceptable salt thereof.
 9. A method of treatment or prevention in amammal of benign or malignant neoplastic disease the method comprisingadministering to a mammal in need thereof a compound of claim 1, or apharmaceutically acceptable salt thereof.
 10. The method of claim 9wherein the benign or malignant neoplastic disease is selected fromuterine myometrial fibroids, endometriosis, benign prostatichypertrophy; carcinomas or adenocarcinomas of the endometrium, ovary,breast, colon, prostate, pituitary, meningioma or otherhormone-dependent tumors.
 11. A pharmaceutical composition comprising apharmaceutically effective amount of a compound of claim 1 and apharmaceutically acceptable carrier or excipient.